Intuitively, this corresponds to inhibiting a larger fraction of Syk, and thus there is less Syk available to propagate a signal

Intuitively, this corresponds to inhibiting a larger fraction of Syk, and thus there is less Syk available to propagate a signal. expanded and used by Perley [3] for cellular level control. Perleys success in using Zhengs model for prediction and open-loop control made it an ideal candidate to adapt for our B cell study. The signaling of B cell and of T cell can be divided into early interactions, which occur proximal to the membrane, and downstream interactions, which occur in the cytoplasm and ultimately lead to the nucleus. The dynamics of the downstream signaling are nearly identical between the cells, and thus this part of the Zheng model remained largely unchanged. The signaling dynamics Delphinidin chloride of T cell and of B cell differ the most in their early signaling, which is where most model revisions were required. In the past decade there have been a number of computational models, both stochastic and deterministic varieties, focusing on various aspects of B cell signaling, but none have considered impairment to Syk and the resulting effect on cell response. Stochastic simulations have been used by Tsourkas [4] and Mukherjee [5] while considering spatial dynamics of BCR signaling. The impact of affinity discrimination was considered by Tsourkas in their study, while Mukherjee investigated the roles of Syk and Lyn in immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation. A deterministic model by Chaudhri [6] considers a scope similar to Zhengs T cell model, with Delphinidin chloride the model covering both membrane proximal, early signaling events and downstream signaling events. This model pays particular interest to the role of phosphatases in the signal transduction. In 2012, Barua [7] developed a deterministic model of B cell early signaling in order to study the feedback loops Delphinidin chloride involving Lyn and how varying stimulation to the BCR leads to a range of dynamics in Syk. Impressively, the model incorporates every phosphorylation event for all six signaling components considered. Our model is novel in its incorporation of Syk-AQL dynamics and given its scope, the inclusion of both early and downstream signaling, this allows us to investigate the impact of Syk modulation on a large number of signaling components. Instead of considering all possible phosphorylations for our 32 signaling components, our model considers only the most critical events in order to represent relevant physiological behavior and minimize model complexity. Understanding the means by which cell responses are determined is also of particular interest and the model will allow us to investigate the impact of both the amount of antigen and the level of Syk activity on the response. In this initial study we HOX11L-PEN are particularly interested in the regulation of Erk and NF-[8] Delphinidin chloride to then determine points in parameter space that allow us to reproduce data from cellular assays. Then, using the difference of Erkp, the sum of singly and doubly phosphorylated Erk, and NF-[6], and finish with some discussion of future direction and limitations. 2. Model Development 2.1. Biological Background Since our B cell model is derived from an existing T cell model, we note here some of the primary components of B cell signaling, with a focus on aspects that are unique to B cells. Conventional T cells bind peptide antigens presented by major histocompatibility molecules whereas Delphinidin chloride B cells can bind multiple molecular species through polymorphic cell surface immunoglobulins that serve as antigen receptors. The B cells work collaboratively with T cells to respond to monomeric antigens or independently of T cells to respond to polymeric antigens that cluster the BCR. Once an antigen is bound and the BCR is aggregated, the signaling mechanisms at the B cell membrane are activated and an intricate system of molecular interactions initiates [9]. There are many kinases involved.

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